This invention relates to azabicyclic compounds. More particularly it relates to pyridone-fused azabicyclic compounds of the formula I below. Compounds of formula I are useful in the treatment of addictive disorders such as the use of tobacco or other nicotine containing products and also for the treatment or prevention of withdrawal symptoms caused by cessation of chronic or long term use of tobacco products. These compounds are also useful in the treatment of Huntington's Chorea, tardive dyskinesia, hyperkinesia, mania, dyslexia, schizophrenia, analgesia, attention deficit disorder (ADD), multi-infarct demetia, age related cognitive decline, epilepsy, neurological and mental disorders related to a decrease in cholinergic function such as Huntington's Chorea, tardive dyskinesia, hyperkinesia, mania, dyslexia, schizophrenia, analgesia, attention deficit disorder (ADD), multi-infarct demetia, age related cognitive decline, epilepsy, neurological and mental disorders related to a decrease in cholinergic function, senile dementia of the Alzheimer's type, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), anxiety, obesity, Tourette's Syndrome and ulcerative colitis.
The compounds of this invention may also be used in combination with a anti-depressants such as imipramine in order to treat both the cognitive decline and depression associated with AD; in combination with serotonin uptake inhibitors such as Zoloft to treat both the cognitive decline and depression associated with AD; in combination with muscarinic agonists in order to stimulate both central muscarinic and nicotinic receptors; in combination with neurotrophic factors such as NGF in order to maximize cholinergic enhancement; in combination with agents which slow or arrest AD such as amyloid or tau inhibitors.
Substances which can deliver pharmacologically relevant amounts of nicotine to the central nervous system are among the most abused substances known. These include, but not are not limited to tobacco cigarettes, and "chewing tobacco" (see J. E. Henningfield, Ph.D, New England Journal of Med., 1196, 1995). Cigarette smoking has been tied to increased risk for lung cancer, emphysema and heart disease and it is estimated 400,000 people will die in 1995 from the combined effects of nicotine abuse in the United States (see J. A. Califano, Jr., New England Journal of Med. 1214, 1995). Nicotine is a highly addicting drug with 40% of those who try smoking later becoming physically dependent upon it. Attempts to quit the use of nicotine, such as in smoking, have been largely ineffective with &gt;80% of such attempts ending in failure. Most attempts to quit end in failure in the first week due to intense withdrawal and craving symptoms. An effective therapy should aid in the cessation or lessening of tobacco use, prevent withdrawal etc prevent withdrawal symptoms, relieve craving and, simultaneously, antagonize the reinforcing effects of nicotine obtained through smoking. Currently, few therapies are available for smoking cessation and most involve replacement of cigarettes with nicotine in the form of a patch or gum. A high rate of relapse and low overall success in ending nicotine use is evidence of the need for additional and more effective therapies for treatment of nicotine addiction than the nicotine patch or gum.
Pharmaceutical compositions employed for the treatment of chronic nicotinism and addiction to nicotine can be divided into two groups. The first covers salts of silver, iron and copper. These substances are employed to develop a negative reflex to smoking usually in the form of a solution, or by incorporation in chewing gum compositions. The resultant reflex is based on the appearance of a strong unpleasant taste in the mouth during smoking after a preliminary rinsing of the mouth cavity with solutions of salts, or after the use of a chewing gum containing such salts (See Nasirov et al. "Anabasine Hydrochloride--New Antismoking Agent", Chemico-Pharmaceutical Journal, vol. XII, 1978, No. 2, 149-152).
The second group of agents that are used for the suppression of nicotine addition comprises substances of an alkaloidal nature, such as 1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one (hereafter 'cytisine), lobeline and anabasine hydrochloride, possessing an effect on H-cholinoreactive systems of the organism similar to that of nicotine. The mechanism of their effect is due to their structural similarity with nicotine and the possible "competitive" antagonism between these alkaloids and nicotine (F. R. Khalikova, S. H. Nasirov, "On pharmacology of the Alkaloid Anabasine and some Polymeric and Copolymeric Derivatives Thereof", in Coll. "Pharmacology of Vegetable Compounds", Proceedings of Tashkent University, 457, 1973, 5-16).
U.S. Pat. No. 4,971,079 describes a composition comprising a biologically resorbable polymer containing a cation exchange group modified by an antinicotine action alkaloid, such as anabasine or cytisine, and a gum containing same. However, it has been found that the potency of cytisine is not high due to its inability to penetrate the brain barrier. (Reavill, C. et al., Behavioural and Pharmacokinetic Studies On Nivotine. Cytisine and Lobeline, Neuropharmacology, 29, 619-624 (1990)). Labadie L. C. ((Peut-on supprimer les facteurs de risque en bronchopatie chronique et en particulier le tabac", Mediater, med., 1976, 4, No. 112, 97, 99)) describes the use of leaves of other night-shade plants, such as potato, tomato, eggplant and digitalis as tobacco substitutes.
One of the most successful approaches to date in reducing the incidence of smoking relies upon nicotine containing chewing gum which is designed to reduce smoking withdrawal symptoms. The reported success rate, while still relatively low, is approximately twice that of the other methods which have heretofore been employed. (See British Medical Journal, 286, (1983)).
The use of the nicotine gum suffers from several problems including bad taste, destruction of dental appliances and gastrointestinal discomfort thereby reducing their use to suppress nicotine addiction. In addition, it has been found that the nicotine containing gum does not completely satisfy the craving that most smokers experience for nicotine and often nicotine gum becomes addictive to the patient.
A simulated smoking device which uses a source of vaporizable nicotine is claimed in U.S. Pat. No. 4, 284,089. While the cigarette itself is non-combustible it delivers a nicotine-containing vapor which may not raise the nicotine level in the blood sufficiently to satisfy a smoker. Thus, it has not been shown to satisfy the desire for a certain nicotine level in the blood to which many smokers have become accustomed and, even more so, upon which many smokers have become dependent. In addition, the simulated smoking devices of the type taught in U.S. Pat. No. 4,284,089 also suffer from the bad taste of a substantial amount of nicotine introduced into the oral cavity. More importantly, this nicotine does not penetrate into the chest for stimulating and providing that sensation normally provided by nicotine and to which the smoker has become accustomed.
The current first line therapy for smoking cessation, as described in U.S. Pat. No. 5,016,652 describes a transdermal patch which is useful for the controlled delivery of nicotine to the bloodstream of the user thereby reducing the incidence of smoking. Clinical trials have shown that abstinence rates (with the nicotine patch) of 30 to 40% can be achieved during the first six weeks of application (K. J. Palmer, M. M. Buckley, D. Faulds; Drugs 44(3) 498-529, (1992) compared with 4 to 21% with a placebo. However, long term abstinence rates (&gt;6 months) are considerably lower; falling to between 11-18%. Thus, a more effective therapy which will afford a greater percentage of smokers who are able to quit is clearly needed.